Membrane sealant Poloxamer P188 protects against isoproterenol induced cardiomyopathy in dystrophin deficient mice

• Published in: BMC cardiovascular disorders Vol. 11; no. 1; p. 20
• Main Authors: Spurney, Christopher F, Guerron, Alfredo D, Yu, Qing, Sali, Arpana, van der Meulen, Jack H, Hoffman, Eric P, Nagaraju, Kanneboyina
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 16-05-2011; BioMed Central; BMC
• Subjects: Adrenergic beta-Agonists; Analysis of Variance; Animal models in research; Animals; Aortic Valve - drug effects; Aortic Valve - physiopathology; Blood Pressure - drug effects; Body Weight - drug effects; Cardiomyopathies - chemically induced; Cardiomyopathies - diagnosis; Cardiomyopathies - metabolism; Cardiomyopathies - physiopathology; Cardiomyopathies - prevention & control; Cardiomyopathy; Cardiovascular Agents - administration & dosage; Cardiovascular Agents - pharmacology; Care and treatment; Collagen - metabolism; Complications and side effects; Disease Models, Animal; Drug Administration Schedule; Duchenne muscular dystrophy; Dystrophin; Dystrophin - deficiency; Dystrophin - genetics; Female; Fibrosis; Genetic aspects; Heart diseases; Heart Rate - drug effects; Injections, Intraperitoneal; Isoproterenol; mdx; Mice; Mice, Inbred mdx; Muscle Strength - drug effects; Muscle, Skeletal - drug effects; Muscle, Skeletal - physiopathology; Muscular Dystrophy, Duchenne - complications; Muscular Dystrophy, Duchenne - drug therapy; Muscular Dystrophy, Duchenne - genetics; Muscular Dystrophy, Duchenne - metabolism; Muscular Dystrophy, Duchenne - physiopathology; Myocardial Contraction - drug effects; Myocardium - metabolism; Myocardium - pathology; Physiological aspects; poloxamer; Poloxamer - administration & dosage; Poloxamer - pharmacology; Risk factors; Stroke Volume - drug effects; Time Factors; Ventricular Function, Left - drug effects; Ventricular Pressure - drug effects; United States
• ISSN: 1471-2261; 1471-2261
• DOI: 10.1186/1471-2261-11-20

Cardiomyopathy in Duchenne muscular dystrophy (DMD) is an increasing cause of death in patients. The absence of dystrophin leads to loss of membrane integrity, cell death and fibrosis in cardiac muscle. Treatment of cardiomyocyte membrane instability could help prevent cardiomyopathy.
Three month old female mdx mice were exposed to the β(1) receptor agonist isoproterenol subcutaneously and treated with the non-ionic tri-block copolymer Poloxamer P188 (P188) (460 mg/kg/dose i.p. daily). Cardiac function was assessed using high frequency echocardiography. Tissue was evaluated with Evans Blue Dye (EBD) and picrosirius red staining.
BL10 control mice tolerated 30 mg/kg/day of isoproterenol for 4 weeks while death occurred in mdx mice at 30, 15, 10, 5 and 1 mg/kg/day within 24 hours. Mdx mice tolerated a low dose of 0.5 mg/kg/day. Isoproterenol exposed mdx mice showed significantly increased heart rates (p < 0.02) and cardiac fibrosis (p < 0.01) over 4 weeks compared to unexposed controls. P188 treatment of mdx mice significantly increased heart rate (median 593 vs. 667 bpm; p < 0.001) after 2 weeks and prevented a decrease in cardiac function in isoproterenol exposed mice (Shortening Fraction = 46 ± 6% vs. 35 ± 6%; p = 0.007) after 4 weeks. P188 treated mdx mice did not show significant differences in cardiac fibrosis, but demonstrated significantly increased EBD positive fibers.
This model suggests that chronic intermittent intraperitoneal P188 treatment can prevent isoproterenol induced cardiomyopathy in dystrophin deficient mdx mice.